liver transplantation for propionic acidemia and ... · management and clinical outcomes authors:...

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This article has been accepted for publication and undergone full peer review but has not

been through the copyediting, typesetting, pagination and proofreading process, which may

lead to differences between this version and the Version of Record. Please cite this article as

doi: 10.1002/lt.25304

This article is protected by copyright. All rights reserved.

Article type : Original Articles

TITLE:

Liver Transplantation for Propionic Acidemia and Methylmalonic Acidemia: Peri-operative

Management and Clinical Outcomes

AUTHORS:

Kristen Critelli1, Patrick McKiernan1,2, Jerry Vockley2,3, George Mazariegos2,4, Robert H

Squires1,2, Kyle Soltys2,4, James E Squires1,2

AFFILIATIONS:

1 Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh of

the University of Pittsburgh Medical Center

2 Center for Rare Disease Therapy, Children's Hospital of Pittsburgh of the University of

Pittsburgh Medical Center

3 Division of Medical Genetics, Children's Hospital of Pittsburgh of the University of


4 Thomas E. Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation,

Department of Transplant Surgery, Children's Hospital of Pittsburgh of the University of


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KEY WORDS:

Organic acidemia, Metabolic liver disease, Hyperammonemia, Pediatrics

ABBREVIATIONS:

CMV: cytomegalovirus

EBV: ebstein-barr virus

GFR: glomerular filtration rate

HAT: hepatic artery thrombosis

IVIG: intravenous immunoglobulin

LKTx: liver-kidney transplant

LTx: liver transplant

MMA: methylmalonic acidemia

MUT: methylmalonyl-CoA mutase

OA: organic acidemias

PA: propionic acidemia

PCC: propionyl-CoA carboxylase

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SD: standard deviation

TCMR: T-cell mediated rejection

tPA: tissue plasminogen activator

CORRESPONDING AUTHOR:

James E Squires MD, MS

Division of Gastroenterology, Hepatology and Nutrition

Children’s Hospital of Pittsburgh

One Children’s Hospital Drive, 6th Floor FP

4401 Penn Avenue

Pittsburgh PA 15224

Phone: 412-692-6406; Fax: 412-692-7355

Email address: [email protected]

ABSTRACT:

Propionic acidemia (PA) and methylmalonic acidemia (MMA) comprise the most common

organic acidemias and account for profound morbidity in affected individuals. While liver

transplant has emerged as a bulk enzyme-replacement strategy to stabilize metabolically

fragile patients, it is not a metabolic cure as patients remain at risk for disease-related

complications. We retrospectively studied liver transplant and/or liver-kidney transplant in 9

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patients with PA or MMA with additional focus on the optimization of metabolic control and

management in the peri-operative period. Metabolic crises were common pre-transplant.

Implementing a strategy of carbohydrate minimization with gradual, but early, lipid and

protein introduction, lactate levels significantly improved over the peri-operative period

(p<0.0001). Post-transplant metabolic improvement is demonstrated by improvements in

serum glycine levels (for PA; p<0.01 x 10-14), methylmalonic acid levels (for MMA;

p<0.0001), and ammonia levels (for PA and MMA; p<0.00001). Dietary restriction remained

after transplant; however no further metabolic crises have occurred. Other disease-specific

co-morbidities such as renal dysfunction and cardiomyopathy stabilized and improved. In

conclusion, transplant can provide a strategy for altering the natural history of PA and MMA

providing stability to a rare but metabolically brittle population. Nutritional management is

critical to optimize patient outcomes.

INTRODUCTION:

Organic acidemias (OA) are a heterogeneous group of inborn errors of metabolism, many of

which are due to disruption of normal amino acid metabolism and result in the accumulation

of toxic intermediary metabolites. Clinical severity can vary, but morbidity is often profound.

While propionic acidemia (PA) and methylmalonic acidemia (MMA) are the most frequent

OA, they are still rare diseases with incidences of 1:240,000 and 1:69,000 in the United

States (U.S) respectively.1 Newborn screening has enabled increased identification of these

diseases in the U.S. and many other countries.2 Under physiologic conditions, propionyl-CoA

is derived from the intestinal flora, branch chain amino acids (valine, methionine, isoleucine,

threonine), and odd-chain fatty acids, then converted to D-methylmalonyl-CoA via the biotin-

dependent enzyme propionyl-CoA carboxylase (PCC). D-methylmalonyl CoA is further

metabolized to succinyl-CoA via consecutive reactions with racemase and the 5-

deoxyadenosylcobalamin (AdoCbl) dependent enzyme methylmalonyl-CoA mutase (MUT),

prior to entering the citric acid cycle for energy production.2

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PA is inherited in an autosomal-recessive fashion due to mutations in either the PCCA or

PCCB genes encoding the alpha and beta subunits, respectively, of PCC. MMA is caused by

complete or partial deficiency of MUT (mut0 enzymatic subtype or mut- enzymatic subtype

respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA,

cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase.3

The clinical presentation of these disorders is that of ‘intoxication type’ neurological distress,

a consequence of accumulating toxic compounds that are produced secondary to the

metabolic block.4 Generally, following an initial symptom-free period ranging from hours to

days after birth, affected neonates with severe disease present with a spectrum of symptoms

including food refusal, vomiting, progressive weight loss, generalized hypotonia, and

abnormal posturing and movements. Progression to lethargy, seizures, and coma can occur,

resulting in severe brain damage and death within a few days if not promptly treated.5 6

Biochemical and laboratory investigations reveal a combination of increased anion gap

metabolic acidosis, leukopenia, thrombocytopenia, elevated lactate, anemia, ketonuria, and

hyperammonemia.5 7 Diagnosis is made by elevated C3 carnitine levels in combination with

specific urine and blood metabolites, and confirmed by enzymatic or molecular studies.8

Treatment strategies are reflective of the clinical state, aimed at addressing the disease

specific complications of the initial acute presentation, long-term management, and

intermittent metabolic decompensations that can occur from various triggers. Recent

comprehensive reviews have been published2 and proposed guidelines are available.8

Ultimately, these management strategies have improved survival but have not modified the

poor neurodevelopmental prognoses for children affected by these disorders.9 Other long-

term complications include selective organ impairment from renal failure (MMA>PA),

pancreatitis (PA>MMA), cardiomyopathy (PA>MMA), and brain basal ganglia infarctions

(MMA>PA).8 The intensity of the medical management combined with frequent

hospitalizations significantly impacts the quality of life of affected children and their families.

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Bulk enzyme supplementation with liver transplant (LTx) as a therapeutic strategy for PA and

MMA was first proposed is the early 1990s.10 Given that the enzymes responsible for PA and

MMA are expressed in all tissues of the body, it was not expected that LTx would provide a

metabolic cure; rather, LTx was proposed as a way to stabilize metabolically fragile patients,

minimize the risk of further decompensations, and improve quality of life.11 More recent

modifications to the organ allocation policies in the U.S. have given priority status to these

disorders based on the risk of sudden life-threatening decompensation. The result has been

the ability to list children with these disorders for transplant based solely on their diagnosis

rather than disease-specific complications or severity.12 Subsequent publications have

reported on the experience of LTx in the management of PA11 13-15 and MMA6 16, and the

application of statistical modeling has shown that LTx may provide a societal benefit over

traditional medical management by increasing both life years lived and quality of life years,

while decreasing cost over a patient’s lifetime.17 However, robust data on transplant

experiences with these rare diseases remains sparse. Thus, we report our center’s

experience with transplant in the management of PA and MMA, with additional focus on the

optimization of metabolic control and management in the peri-operative period.

PATIENTS AND METHODS:

Children with a diagnosis of PA or MMA who underwent either a LTx or liver-kidney

transplant (LKTx) at the Children’s Hospital of Pittsburgh of UPMC were identified from the

patient database; their demographic, clinical, and laboratory data, including medical

treatment prior to transplantation, indications for transplantation, pre-LTx assessment, early

management in intensive care unit, as well as long-term follow-up were analyzed. Renal

function was determined with estimated glomerular filtration rates (eGFR; categorized as

mild [60 to < 90 ml/min/1.73 m2], mild-to-moderate [45-59 ml/min/1.73 m2], moderate-to-

severe [30-44 ml/min/1.73 m2], and severe [15-29 ml/min/1.73 m2])18 using the creatinine-

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based Schwartz equation19 before LTx, or measured via radionuclide or serum cystatin C

levels (normal <1.1 mg/dL). For analysis of peri-operative metabolic control, glycine was

chosen as a PA-specific marker while serum methylmalonic acid was used to reflect MMA

patients. For analysis of post-transplant serum lactate levels, ‘early’ measurements were

defined as lactate levels obtained within the first week following transplant; ‘late’ levels were

defined as those obtained at normalization, discharge, or 4 weeks following transplant,

whichever occurred first. At least 3 recordings were included in each group for each patient.

Continuous data that were normally distributed are presented as the mean plus or minus the

standard deviation (SD), and were analyzed by the two-tailed Student t test. Differences

were considered statistically significant if the p value was < 0.05.

All information was gathered on a standardized form. Data were de-identified and coded by

study number in accordance with the Health Insurance Portability and Accountability Act

guidelines. The study was approved by the Institutional Review Board at the University of

Pittsburgh.

RESULTS:

Patient Characteristics: Nine transplants were performed for the indication of either PA (n=3)

or MMA (n=6) between 2006 and 2017 with 100% patient and graft survival with mean follow

up period of 3.5 year (range 1 – 11.6). Five were female. Five of 9 patients had a genetically

confirmed diagnosis. In the 3 MMA patients without documented genetic mutations, the

patients were characterized as MUT0 based on enzymology. In the PA patient without a

genetic confirmation (patients 3), the diagnosis was based on clinical presentation,

biochemical abnormalities, and a history of a sibling with a genetic diagnosis with common

parents. Five patients were born in the U.S., 2 patients were referred from Saudi Arabia, and

2 were from Qatar. Four subjects (patients 1,4,6, and 8) were diagnosed via expanded

newborn screening. Within the analyzed cohort, there was one sibling relationship (patients

2 and 3). Consanguinity was present in all 3 patients with PA. (Table 1)

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Pre-transplant Characteristics and Clinical Course: Eight of the 9 (88.9%) children initially

presented within the first week of life, the exception being patient 7 who presented at 248

days of life with projectile vomiting, poor feeding, failure to thrive, and developmental delay.

(Table 1) Metabolic crises were common in most patients, often requiring hospitalization with

supportive care despite optimal medical management. All patients were treated with protein

restriction and carnitine supplementation. Medications to reduce blood ammonia levels

included N-carbamylglutamate (n=3) and sodium benzoate (n=1). Metronidazole was

frequently used, as was sodium citrate and trisodium citrate. The median protein restriction

at the time of referral for transplant was 1.6 g/kg/day (range 0.98-2.6 g/kg/day), and 8/9

required supportive feeding via a surgically placed gastrostomy tube.

Baseline liver, metabolic, and renal function studies are presented. (Table 1) Five of 6

patients with MMA were noted to have evidence of kidney impairment. Mild (patients 6 and

8), mild-to-moderate (patient 4), and moderate-to-severe (patients 5 and 7) injury was

present in the cohort. Consistent with the disease processes, liver-specific biochemistries

were relatively normal with only mild aminotransferase elevations noted in a minority of

subjects (patients 3, 5, 6, and 8). Synthetic function (total bilirubin and INR) was normal in all

cases. Serum glycine (mean 1023.9 umol/L, SD 343.4) and methylmalonic acid (mean 745

umol/L, SD 704.3) were elevated in PA and MMA patients respectively. Hyperammonemia

was common (mean 57.4 umol/L, SD 29.1). Neurological and developmental deficits were

frequently present in the cohort. (Table 2) Additional disease related complications included

dilated cardiomyopathy requiring pressor support (patient 1), metabolic stroke (patient 6),

pancreatitis (patients 2 and 8), and pancytopenia (patient 6).

Peri-operative Characteristics and Clinical Course: Peri-operative characteristics and related

complications are noted. (Table 3) At the time of transplantation, the median age was 9.3

years (range 1.2 - 21.6 years). LKTx was performed in 5 of 6 patients with MMA while all PA

patients received LTx alone. Whole liver grafts were used in 6 of 9 patients (5 were

associated with LKTx). Living donation was utilized in 2 patients (patients 1 and 2).

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Comprehensive anesthetic management, while an important consideration in this population,

was unable to be thoroughly collected from the medical record. However, no patients were

reported to require perioperative continuous hemodiafiltration. The median length of stay in

the intensive care unit was 29.7 days while the entire transplant-related hospitalization

averaged 55 days.

Vascular Complications: Hepatic artery thrombosis (HAT) occurred in 2 patients.

Intraoperatively, patient 9 developed a hepatic artery thrombus, necessitating Fogarty

catheter thrombectomy followed by tissue plasminogen activator (tPA) chemical

thrombolysis with successful revascularization. Lovenox therapy was implemented for nine

months prior to switching to aspirin. Patient 1 developed a recurrent left hepatic arterial

thrombosis that did not resolve despite placement of an aortic conduit graft, resulting in an

associated hepatic allograft infarction. Patient 5 developed a near-complete stenosis of the

right hepatic vein at its junction with the inferior vena cava, which was managed with hepatic

venoplasty and anticoagulation.

Metabolic Control: Serum lactate levels, as a reflection of metabolic control, significantly

improved during the first post-transplant month. (Figure 1) Early serum lactate levels,

collected over the first week following transplant, were universally elevated (mean level 5.2

umol/L, range 2.3 – 10.6). Late lactate levels (defined as those obtained at normalization,

discharge, or 4 weeks following transplant, whichever occurred first) were significantly

improved compared to the earlier levels (mean level 2.9 umol/L, range 1 – 6.8). These

findings were present in both the PA and MMA cohorts. (Figure 1)

Long-term Characteristics and Clinical Course: Metabolic and transplant related outcomes

over a mean follow up period of 3.5 year (range 1 – 11.6) are presented. (Tables 3 and 4)

Patient and graft survival were 100%.

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T-cell Mediated Cellular Rejection: T-cell mediated rejection (TCMR) of the hepatic allograft

was common with 15 episodes (14 histologically confirmed) occurring in 6 of 9 patients

within cohort. Patient 7 was noted to have one episode of renal rejection. Rejection episodes

were primarily treated with steroids and increased immunosuppression (with or without

adding additional immunosuppressive agents). Only patient 7 required anti-lymphocyte

therapy for a steroid-unresponsive rejection episode that occurred 4 months post-transplant.

Biliary Complications: Biliary complications were noted in both patients with HAT (patients 1

and 9). Additional biliary anastomotic strictures (patient 2 with biliary-enteric stricture, patient

4 with biliary anastomotic stricture) were noted. Percutaneous transhepatic biliary drainage

catheter placement and serial balloon dilatations have been required in all cases. At last

follow-up, only patient 4 remained with an in-dwelling biliary catheter secondary due to

recurrent anastomotic and central bile duct stricturing.

Viremia: Patient 1 developed cytomegalovirus (CMV) viremia requiring intravenous

ganciclovir with resultant downtrend in CMV titers. Four children (patients 2, 3, 4, and 8)

developed Ebstein-Barr virus (EBV) viremia necessitating intravenous immunoglobulin

(IVIG) therapy, rituximab, and/or a decrease in immunosuppressive therapy with resultant

downtrend in EBV titers. No patient developed suspected or confirmed post-transplant

lymphoproliferative disorder.

Nutrition and Metabolic Related Outcomes: All patients with PA remain on amino acid-

modified supplementation (Propimex-2, Abbott ®). (Table 4) Of the 6 MMA patients, all

persist with protein diet restriction but with stable methylmalonic acid and ammonia levels, 2

remained on a metabolic formula with a natural protein restriction to 1 g/kg/day, 1 patient

had a protein intake of 1.35 g/kg/day protein, and 1 patient was on a low-protein diet at the

time of their last follow-up visit. All patients continued to receive carnitine supplementation

and no patient had suffered further metabolic crises in the post-transplant period. Post-

transplant metabolic improvement is further demonstrated by improvements in serum glycine

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levels (for PA), methylmalonic acid levels (for MMA), and ammonia levels (PA and MMA).

Mean serum glycine (1023.9 umol/L vs. 259.1 umol/L; p<0.01 x 10-14), methylmalonic acid

(745 umol/L vs. 154.9 umol/L; p<0.0001), and ammonia levels (57.5 umol/L vs. 40.9 umol/L;

p<0.00001) were significantly lower in the post-transplant period. (Figures 2 and 3) Patient

7 did receive additional administration of adenylcobalamin and hydroxycobalamin as part of

a clinical trial aimed at optimizing metabolic management after transplantation.

Other: Renal function had stabilized or improved in all MMA patients following transplant

(pre-transplant vs post-transplant mean eGFR: 104.6 vs 111.4; p=0.8). Patient 7 did undergo

a renal biopsy 17 months post-LKTx, which showed mild tubulointerstitial injury, consistent

with the diagnosis of MMA and tacrolimus toxicity. In patient 1 with severe dilated

cardiomyopathy and left ventricular dilation and dysfunction pre-transplant, clinical and

echocardiographic improvements were noted with improved cardiac dilatation and left

ventricular function noted on cardiac assessment 2 years following his transplant.

DISCUSSION:

PA and MMA cause life-threatening metabolic decompensation episodes and can result in

serious sequelae. Although early detection with expanded newborn screening protocols and

improvements in conventional substrate reduction therapy have led to an overall decrease in

mortality, growth retardation and failure, poor nutritional status, selective organ impairment,

and accumulative neurologic injury are persistent disease complications.2 6 8 20-24

LTx (for PA and MMA) or LKTx (for MMA) has shown efficacy in reducing and/or eliminating

the risk of metabolic decompensation and markedly improves the quality of life of patients.6 8

11 14 20 As such, transplant is now a commonly accepted therapeutic option for individuals

with these devastating conditions.25 Still, hesitancy remains largely due to incomplete

metabolic control and the persistent (albeit reduced) risk of organ damage.26 Our experience

with transplant in PA and MMA highlights early difficulties in perioperative and postoperative

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metabolic management, but ultimately complete resolution of episodes of metabolic

decompensation. We further seek to recommend considerations for early post-operative

metabolic management based on our experience.

In our series, we show a 100% patient and graft survival in a cohort of 9 individuals

transplanted with an underlying diagnosis of PA (n=3) or MMA (n=6) with a mean follow up

period of 3.5 years. For MMA, this is similar to other recent reports.6 27 While our cohort is

small, our experience with zero mortality with PA and LTx stands in contrast to reports of

high mortality rates following transplant.13 28 Still, perioperative complications were common,

underscoring the complexity of these diseases. Multiple confounders have been suggested

to influence clinical outcomes after transplant, including age, center experience, and co-

morbid conditions associated with the underlying disease.6 13 Four of 9 patients (44%) in our

series were noted to have a significant perioperative complications, with the majority being

vascular in nature (2 HAT and 1 hepatic vein/IVC stenosis). An additional 2 patients had

biliary strictures which required intervention during the follow up period. While no HAT was

noted in these patients during the perioperative period, compromised blood flow is a known

risk for late biliary complications.29 As such, future efforts to better understand the

relationship between these OA and transplanted-related vascular and biliary complications

are needed.

Surgical considerations in this complex patient population include optimal graft selection to

enhance chances of immediate wound closure and early extubation. More aggressive HAT

prophylaxis is our practice based on earlier published experience demonstrating increased

risk of thrombotic complications.

A primary indication for transplant in these disorders is to stabilize the medically fragile

patient. Following transplant, markers of metabolic control in our patients were improved in

both the early peri-operative and long-term in the post-operative periods. The importance of

appropriate metabolic support in the setting of PA and MMA is well recognized2 8 11 and

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recent reports have highlighted the pre-operative and anesthetic considerations that

complicate the transplant operation.30-33 As with the management of the disease prior to

transplant, it is imperative that the immediate post-operative treatment minimizes catabolism

to avoid metabolic decompensation. Clearly, the addition of partial enzyme replacement via

a liver transplant enables a ‘re-setting’ of the patient’s metabolic fitness. Close monitoring is

critical as fluids and nutritional support are introduced and adjusted in the early post-

operative period. Lactate has been shown to be the most reliable parameter reflecting

appropriate metabolic control. 8 34 Our center’s approach to the nutritional support of patients

following transplant has been to gradually ease protein restriction toward the establishment

of a new patient-specific baseline in the long-term. In the early postoperative period

promoting anabolism is problematic in the setting of early liver dysfunction and lactic

acidosis associated with the transplant process itself combined with the frequent use of

corticosteroids. There is intolerance of high-dose carbohydrate and the use of insulin tends

to exacerbate lactic acidosis. Our practice has been to aim for carbohydrate infusion rates of

approximately 8 mg/kg/min, in combination with the introduction of protein (0.5 g/kg/d) and

lipid (1 g/kg/d) from day 1. We aim to meet full lipid (2 g/kg/d) and protein intake (2 g/kg/d)

on day 4 depending on the overall clinical and metabolic picture. This general approach has

been successful given that serum lactate levels significantly improve over time post-

transplant. Long-term, we show improvements in serum glycine (for PA), methylmalonic acid

(for MMA), and ammonia (for PA and MMA) following transplant, even with increased protein

intake, consistent with other reports. Importantly, caution must be taken in attempting to over

protocolize post-transplant support. Multiple patient and graft related factors, including

surgical and hospital-related stressors contribute to the need to individualize and adjust

medical and nutritional support. Finally, our experience adds to the emerging understanding

that metabolic crises recurrence can be all but eliminated following transplant.

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Our study was limited by its size and retrospective nature. Most of the patients did not

receive their pre-transplant metabolic care at our institution, restricting the amount of clinical

data that was available for review. Further, while lactate has been shown to be a good

indicator reflective of metabolic control, lack of routine testing once patients were in the

outpatient setting limited its use for more long-term analysis. Additionally, many of the

confounders that can affect lab values, such as tourniquet application, use of central venous

catheters vs peripheral access, temperature perturbations of the sample, and processing

delays are unknown and unavailable for assessment. Furthermore, while glycine used as a

marker of disease control, medications such as sodium benzoate may have affected these

levels by lowering what was recorded in the medical chart. As such, the preciseness of the

data may be affected. Pre-transplant developmental testing was not uniform and post-

transplant testing was not performed routinely. Finally, the medical record did not enable a

thorough collection of nutritional support over the early post-transplant course. Percentages

of enteral feeds, TPN, intravenous fluids, and per os intake were unable to be accurately

quantified on any given day and what was ordered in the chart was not always reflected

accurately in the medical record. Future efforts would benefit from more acute focus on the

peri-operative nutritional management, likely in a prospective study.

In conclusion, we report a 100% survival in 9 patients and 14 transplanted organs (4 LTx

and 5 LKTx) in a cohort of patients with PA and MMA. Peri-operative and long-term

complications are common, highlighting the medical complexity of these diseases. Well-

recognized disease specific complications such as kidney disease (MMA) and

cardiomyopathy (PA) improved and stabilized; and no patient developed disease related

metabolic crises following transplant. While long-term dietary restriction cannot truly be

normalized in these patients, we demonstrated that with close monitoring by an experienced

multidisciplinary team, relaxed dietary protein restriction can safely occur early following

transplant. Additional follow-up is required to determine if continued liberalization of dietary

constraints is attainable in the long-term. Importantly however, is the recognition that

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transplant does not fully correct the metabolic perturbations, and that patients still have

massive elevations of the OAs in the blood and organs after transplant. Therefore, while

dietary protein tolerance is improved, the monitoring of, and restriction to the recommended

dietary allowance, of the total protein intake should be practiced.

FIGURE LEGENDS:

Figure 1. Early vs late serum lactate level post-transplant in PA and MMA. Early lactate

levels were within 1 week following transplant. Late levels were defined as those obtained at

normalization, discharge, or 4 weeks following transplant, whichever occurred first.

Significant improvement was noted as protein restriction was lifted and nutritional support

advanced. Early levels for PA: mean 5.9 umol/L vs late levels: mean 2.1 umol/L; p<0.0001.

Early levels for MMA: mean 5.0 umol/L vs late levels: mean 3.3 umol/L; p<0.001. Early

levels for all: mean 5.22 umol/L vs late levels: mean 2.88 umol/L; p<0.000001.

Figure 2. Pre- and Post-transplant serum glycine and methylmalonic acid levels. Mean

serum glycine (1023.9 umol/L vs. 259.1 umol/L; p<0.01 x 10-14) and methylmalonic acid (745

umol/L vs. 154.9 umol/L; p<0.0001) levels in the pre- and post-transplant periods.

Figure 3. Pre- and Post-transplant serum ammonia levels for PA cohort (53.2 umol/L vs.

37.7 umol/L; p<0.01), for MMA cohort (60.8 umol/L vs. 41.8 umol/L; p<0.0001), and all

patients (57.5 umol/L vs. 40.9 umol/L; p<0.00001) show significantly lower levels in the post-

transplant period.

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Table 1: Baseline Patient Characteristics

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9

Diagnosis PA PA PA MMA MMA MMA MMA MMA MMA

Genetic homozygous

mutation in

exon 8 of the

PCCB gene

(c.877

G>ApD293N

homozygous

PCCA p.G117D

gene mutation

**

homozygous

c.23delG

mutation in

the MMAB

gene

¶

homozygous

mutation,

c.607G>A

(p.G203R)

¶

¶

Two MUT 0

heterozygous

pathogenic variants,

c.655A>T (p.N219Y)

and c862T>C

(p.S288P)

Gender Male Female Male Male Female Female Female Male Female

Age at presentation

(days) 7 Neonatal period 0 (+FHx) 3 (+FHx) 4

Neonatal

period 248 0 (+FHx) 2

Consanguinity Yes Yes Yes Unknown No Unknown No No No

Echocardiogram Abnormal£

Abnormal££

Normal Normal Normal Normal Normal Normal Normal

eGFR

(mL/minute/1.73 m2)* 176 194 134 56 40 66.2 40 65 96.8

AST IU/L (IQR) 24 (8.5) 36.5 (17.25) 30 (45) 36.5 (19.75) 131 (128.7) 77 (39.5) 21.5 71 (9) 47 (24.5)

ALT IU/L (IQR) 21 (4) 22.5 (6.5) 20 (53.5) 23.5 (18.25) 60.5 (50.2) 68 (42) 17.5 59 (8) 37 (19.5)

Total bilirubin mg/dL

(IQR) 0.7 (0.35) 0.65 (0.38) 0.8 (0.5) 0.6 (0.35) 0.5 0.65 (0.43) 0.4 0.6 (0.7) 0.4 (0.1)

GGT IU/L (IQR) 15 (3.25) 13 23 23.5 (13.4) 75.5 (51.6) 62 (73) 10.5 56 15

INR (IQR) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1) 1 1.2 (0.1) 1 1.1 1 (0.2)

Ammonia umol/L

(IQR) 29 (15) 56 (26.5) 54.5 (26.8) 54 (42) 34 (10) 75 (42) 54.5 32 (13) 40.5 (24.5)

Glycine umol/L (IQR)¥ 968 (703.25) 810 (490.5) 1280 (320) - - - - - -

MMA umol/L (IQR)¢ - - - 1190 (998.5) 836 433 (219) -

2830

(424.3) 265 (303.5)

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Total protein intake

(g/kg/day) 1.55-1.85 1.5-1.8 1.6-1.7 1.6-2.0 1.45-1.75 1.6-2.0 1.3 0.98-1.18 1.8-2.6

Natural protein intake

(g/kg/d) 0.86-0.92 None None 0.67-0.73 - None None 0.98-1.18 0.83

Gastrostomy feeds

required Yes Yes Yes Yes Yes Yes No Yes Yes

Carnitine

supplementation Yes Yes Yes Yes Yes Yes Yes Yes Yes

Ammonia-lowering

agents Yes Yes Yes No No Yes No Yes No

Pre-transplant

metabolic

complications -

Frequent

(admission every

2-5 months) -

Frequent

(including

PICU

admission)

Frequent

(including

PICU

admission)

Admission at 5

years

Frequent (40+

admissions,

including

PICU)

Frequent

(20+

admissions)

PICU admission at 15

months of age

GFR-Glomerular filtration rate; AST-aspartate aminotransferase; ALT-alanine aminotransferase; GGT-gamma glutamyltransferase; INR-international normalized ratio; SD-standard deviation

¶ No mutation in record – but classified as MUT0 based on enzymology

* GFR obtained prior transplant

** Diagnosis partly based on sibling with positive genetic diagnosis (Patients 2 and 3 are siblings)

¥ Upper limit of normal 140-350 umol/L

¢ Upper limit of normal 0.08-0.56 umol/

£ Severely dilated left ventricle with severely depressed left ventricular systolic function

££ Trivial mitral valve insufficiency

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Table 2: Pre-Transplant Neurocognitive Deficits in PA and MMA



Pre-Tx developmental

delay

No formal

testing Moderate Mild Mild

Extremely-

low to

borderline Moderate-to-severe Mild

No formal

testing Borderline

Age at testing (years)

11.8 0.8 - - - 15.2 - 0.5

Test(s) - DAS II

School Age

assessment

Mullen

Scales of

Early

Learning

- Adaptive

Behavior

Assessment

System-II

(ABAS-II)

The Child

Behavioral

Checklist, Behavior

Rating Inventory of

Executive Function-

Patient Form,

Connors’ Parent

Rating Scale-

Revised

Abbreviated Battery IQ of the

Stanford-Binet Intelligence

Scales, Peabody Picture

Vocabulary Test, Wide Range

Assessment of Memory and

Learning, Developmental Test

of Visual Motor Integration,

Woodcock-Johnson Tests of

Achievement, Grooved

Pegboard Test, Delis-Kaplan

Executive Function System,

Child Behavior Checklist,

Conners' Parent Rating Scale

- Bayley Scales

of Infant and

Toddler

Development

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Table 3: Transplant and related complications in PA and MMA



Age at LTx

(years)

8.7 11.8 1.2 6.6 21.6 7.4 15.5 9.4 1.9

Indication for

LTx

Dilated CM

w/ resultant

HF

Metabolic

decompensations

w/ CNS

complications

FHx FHx/metabolic

decompensations/

CKD

Metabolic

decompensations

w/ CKD

Metabolic

decompensations w/

CNS

complications/CKD

Metabolic

decompensations/CKD

Metabolic

decompensations/CKD

Preemptive

treatment

Transplant type Orthotopic

split liver

Orthotopic domino

liver

Orthotopic

split liver

Kidney/split liver Kidney/liver Kidney/liver Kidney/liver Kidney/liver Orthotopic split

Liver

Donor graft

type

Living-

related

Living-unrelated Cadaveric Cadaveric Cadaveric Cadaveric Cadaveric Cadaveric Cadaveric

Intensive care

stay (days)

107 11 53 13 29 3 12 8 31

Hospital stay

(days)

184 20 62 35 67 25 27 23 52

Complications HAT Colonic

perforation

Stenosis of R

hepatic vein/IVC

HAT (successful

revascularization)

CM-cardiomyopathy; HF-heart failure; CNS-central nervous system; FHx-family history; CKD-chronic kidney disease; HAT-hepatic artery thrombosis; ACR-acute cellular rejection; IVC-inferior vena cava

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Table 4: Outcomes following transplant in PA and MMA



T-cell Mediated Rejection No Yes Yes No Yes Yes Yes No Yes

Biliary Stricture Yes Yes No Yes No No No No Yes

Echocardiogram Abnormal£ Abnormal££ Normal Abnormal£££ Normal Not done Not done Not

done

Not done

eGFR (mL/minute/1.73 m2) 160 135 134 78 70 142 68 88 128

Cystatin C (mg/L) 1.09 0.9 0.99 - - - 1.19 0.98 -

Total protein intake

(g/kg/day)

1.2-1.5 1.5 2 1 1.0-1.1 1.43 0.76-0.95 1.3-1.5 1.0-1.2

Intact protein (% total daily

protein intake)

100 75 90 100 80 69 - - 100

Carnitine supplementation Yes Yes Yes Yes Yes Yes Yes Yes Yes

Follow-up (years) 2.5 2.1 1.7 3.1 1.6 4.1 11.6 3.6 1

Age at last follow-up (years) 10.8 13.9 2.8 9.7 23.2 11.7 24.1 12.9 2.9

GFR-glomerular filtration rate

£ Mildly dilated left ventricle, mildly decreased left ventricular function, and mild stenosis of inferior vena cava-right atrial junction

££ Trivial to mild mitral regurgitation and trivial tricuspid regurgitation

£££ Mild biventricular dilatation and trace pericardial fluid

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liver transplantation for propionic acidemia and ... · management and clinical outcomes authors:...

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